tbuckley/cabot-search huggingface dataset:
Radiotherapy-Related Dose and Irradiated Volume Effects on Breast Cancer Risk Among Hodgkin Lymphoma Survivors
Authors: Sander Roberti, Flora E van Leeuwen, Cécile M Ronckers, Inge M Krul, Florent de Vathaire, Cristina Veres, Ibrahima Diallo, Cécile P M Janus, Berthe M P Aleman, Nicola S Russell, Michael Hauptmann
Journal: JNCI Journal of the National Cancer Institute (2022)

Abstract Background Breast cancer (BC) risk is increased among Hodgkin lymphoma (HL) survivors treated with chest radiotherapy. Case-control studies showed a linear radiation dose-response relationship for estimated dose to the breast tumor location. However, these relative risks cannot be used for absolute risk prediction of BC anywhere in the breasts. Furthermore, the independent and joint effects of radiation dose and irradiated volumes are unclear. Therefore, we examined the effects of mean breast dose and various dose-volume parameters on BC risk in HL patients. Methods We conducted a nested case-control study of BC among 5-year HL survivors (173 case patients, 464 matched control patients). Dose-volume histograms were obtained from reconstructed voxel-based 3-dimensional dose distributions. Summary parameters of dose-volume histograms were studied next to mean and median breast dose, Gini index, and the new dose metric mean absolute difference of dose, using categorical and linear excess odds ratio (EOR) models. Interactions between dose-volume parameters and mean dose were also examined. Results Statistically significant linear dose-response relationships were observed for mean breast dose (EOR per Gy = 0.19, 95% confidence interval [CI] = 0.05 to 1.06) and median dose (EOR/Gy = 0.06, 95% CI = 0.02 to 0.19), with no statistically significant curvature. All metrics except Gini and mean absolute difference were positively correlated with each other. These metrics all showed similar patterns of dose-response that were no longer statistically significant when adjusting for mean dose. No statistically significant modification of the effect of mean dose was observed. Conclusion Mean breast dose predicts subsequent BC risk in long-term HL survivors.
P953: PHASE I STUDY OF TQB3602 CAPSULE, AN ORAL PROTEASOME INHIBITOR, IN RELAPSED/REFRACTORY MULTIPLE MYELOMA
Authors: W. Tang, Y. Li, X. Zhong, Q. Liang, Y. Liu, Y. Zeng, B. Fang, L. Zheng, T. Niu
Journal: HemaSphere (2022)

Background: The proteasome inhibitor is an effective treatment strategy for multiple myeloma (MM). TQB3602 is a novel oral proteasome inhibitor derived from multiple rounds of optimization based on ixazomib. It has an addition of an acridine ring to the structure of ixazomib, which maintains high activity and selectivity, resulting in better metabolic stability. In preclinical models of MM, TQB3602 displayed potent kinase inhibiting activity for 20S proteasome enzyme with IC50 15.3 nM. It also inhibited cell proliferation in the MM.1S cell line with IC50 10.1 nM. In the MM.1S MM CB-17 CDX model, TQB3602 also showed antitumor efficacy. TQB3602 represents a promising clinical candidate for treating MM. Aims: This study presents the first-in-human trial designed to evaluate the safety, tolerance, pharmacokinetics, dose-limiting toxicity and maximum tolerated dose of TQB3602 in relapsed/refractory MM (RRMM). Methods: This study is a multicenter, open-label, 3 + 3 dose-escalation phase I trial (NCT04275583). Adult patients with RRMM who had received at least two kinds of therapy, including bortezomib, lenalidomide or thalidomide, are enrolled. TQB3602 is orally administered at a dose of 0.5mg, 1mg, 2mg, 3mg, 4mg, 5mg, 5.5mg, 6mg or 7mg on days 1, 8, 15 in 28-day cycle until limiting toxicity or disease progression. Results: Twenty-five patients with RRMM (16 males, 9 females, median age 65, range 37-73) were enrolled between May 2020 and October 2021, with all patients exposed to bortezomib and three patients exposed to ixazomib. Patients received a median of three cycles of TQB3602 (range 1-11). Grade ≥3 drug-related adverse events included anemia (28%), thrombocytopenia (8%), neutropenia (8%) and diarrhea (4%). No grade ≥3 drug-related peripheral neuropathy occurred. Two dose-limiting toxicities occurred at 7mg, including diarrhea and grade 2 peripheral neuropathy. The maximum tolerated dose was determined as 6mg. TQB3602 was rapidly absorbed, resulting in a time to plasma peak concentration from 0.8 to 1.5 hours. After multiple dosing, the terminal half-life was 23 to 152 hours. Following administration of 6 mg, the mean half-life was approximately 82 hours. TQB3602 slightly accumulated in the human body. At a dose of 6 mg, the AUClast and Cmax were approximately 1.9 times higher on day 15 than day 1. The mean plasma concentration-time profiles of day 1 and day 15 are shown in Figures A and B, and the geometric mean plasma Cmax and AUClast on day 1 and day 15 are shown in Figures C and D. Among 25 response-evaluable patients, 65% of patients achieved stable disease or better. Image:Summary/Conclusion: TQB3602 is well tolerated with no severe neuropathy adverse events and has shown preliminary efficacy in patients with RRMM. Based on the efficacy, safety, and pharmacokinetic data, 6mg was recommended as the anticipated therapeutic dose and adopted in an ongoing dose-expansion phase.
Distinct roles of the meningeal layers in CNS autoimmunity
Authors: Arianna Merlini, Michael Haberl, Judith Strauß, Luisa Hildebrand, Nafiye Genc, Jonas Franz, Dmitri Chilov, Kari Alitalo, Cassandra Flügel-Koch, Christine Stadelmann, Alexander Flügel, Francesca Odoardi
Journal: Nature Neuroscience (2022)
PB2333: BURDEN OF HOSPITALIZATION, COSTS AND CO-MORBIDITIES IN MEDICARE PATIENTS WITH CHRONIC GRAFT VERSUS HOST DISEASE: ANALYSIS OF NATIONAL IN-PATIENT HOSPITAL DATABASE
Authors: S. Aggarwal, S. Kumar, A. Bela, O. Topaloglu
Journal: HemaSphere (2022)

Background: Chronic graft-versus-host disease (cGvHD) is a severe complication of allogeneic hematopoietic stem cell transplantation that affects various organs leading to a reduced quality of life. Aims: To analyze trends in hospital length of stay, total costs and co-morbidities in Medicare patients with Chronic Graft Versus Host Disease (CGVHD). Methods: The National Inpatient Sample (NIS) data set from the Healthcare Cost and Utilization Project was utilized in order to determine the number of hospital admissions for Chronic Graft Versus Host Disease. Thirty co-morbidities were assessed using Elixhauser scoring. The outcomes assessed included length of stay (LOS), total charges, co-morbidity score, mortality rate and emergency room visits. Results: There were an estimated 5950 hospitalizations with a diagnosis of CGVHD, with 44% of the patients being covered by Medicare. The mean age was 57 (SD 14.54) years and 41% of the patients were female. The mean hospital length of stay for Medicare patients with CGVHD was 9.29 (SD 15.17) days (Median was 5 days). The mean hospital charges were $108,875 (SD $245171). The mean comorbidity score was 3.74 (SD 1.88, Median score was 4). The in-hospital mortality rate was 6.38%. The vast majority of the patients were White (79%), followed by Hispanic (9%), Black (7%) and Asian (2%). The top five co-morbid conditions were Fluid and Electrolyte Disorders (45%), Hypertension (39%), Depression (26%), Chronic Pulmonary Disease (25%) and Renal Failure (24%). The top 3 primary diagnosis codes were for Sepsis, Complications of stem cell transplant and Pneumonia. Summary/Conclusion: Chronic Graft Versus Host Disease poses significant burden on Medicare with high hospital charges and long LOS. There is a need for new treatment options for cGVHD patients.
PB1824: IMPACT OF DAY 15 BONE MARROW ASPIRATION ON PREDICTION OF COMPLETE REMISSION AND RELAPSE IN ACUTE MYELOID LEUKEMIA
Authors: R. Kharrat, O. Charef, R. Berred, A. Chabaane, S. Sammoud, M. Bchir, F. Ben Lakhal, S. Feki, W. Borgi, E. Gouider, A. Amouri, W. Ayed, H. Ben Neji, B. Meddeb
Journal: HemaSphere (2022)

Background: Although all the progress made in hematology in the last decades, the treatment of acute myeloblastic leukemia (AML) is still disappointing with long term survival which does not extend 40%. Aims: The aim of our study is to assess the impact of early bone morrow blast (BMB) clearance in prediction of complete remission and relapse risk in acute myeloid leukemia Methods: We conducted a retrospective study including patients with AML treated with standard induction chemotherapy (3 days of idarubicine 12mg/m2 and 7days of cytarabine 200mg /m2) at the department of hematology at Aziza Othmena Hospital in Tunisia during 2020 - 2021. Results: Thirty four patients were included. The median age was 41 (range 17-57) and sex ratio was 1.5 (22M/12F). At the time of diagnosis, the median of white blood cells count was 57.8G/L (range 0.76-300G/L) and cytogenetic data were available for 91% of patients. According to cytogenetic stratification, our patients were classified as favorable in 29%, intermediate in 45.1% and unfavorable risk in 25.8% of cases. At the end of induction course, complete remission (CR) was achieved in 64% of patients. Induction related mortality was 8.8%. The most common cause of death was infection (66%). Bone morrow aspiration at day 15 was performed for all our patients. Only one patient had re-induction at day 18. Fifteen patients (44%) had more than 5% BMB in day 15. 53% of patients with more than 5% BMB did not achieve a CR compared to 18% with less than 5% BMB. (p=0.05) Induction related mortality was not affected by the results of BMB in day 15. However, the relapse rate was significantly higher in the group of patients with more than 5% BMB at day 15 compared with the other group (66% vs 0%; p=0.002). Summary/Conclusion: Our study showed a significant statistical relation between BMB at day 15 and relapse risk. Thus, the kinetic of bone morrow blast clearance could be correlated to the minimal residual disease at the end of induction and so could predict the risk of relapse.
Effects of gender-transformative relationships and sexuality education to reduce adolescent pregnancy (the JACK trial): a cluster-randomised trial
Authors: Maria Lohan, Aoibheann Brennan-Wilson, Rachael Hunter, Andrea Gabrio, Lisa McDaid, Honor Young, Rebecca French, Áine Aventin, Mike Clarke, Clíona McDowell, Danielle Logan, Sorcha Toase, Liam O’Hare, Chris Bonell, Katie Gillespie, Aisling Gough, Susan Lagdon, Emily Warren, Kelly Buckley, Ruth Lewis, Linda Adara, Theresa McShane, Julia Bailey, James White
Journal: The Lancet Public Health (2022)

The need to engage boys in gender-transformative relationships and sexuality education (RSE) to reduce adolescent pregnancy is endorsed by WHO. We aimed to test an intervention which used a gender-transformative approach to engage adolescents in RSE to prevent unprotected sex.This cluster-randomised trial with process and economic evaluations tested a school-based intervention entitled If I Were Jack versus standard RSE (control) for students (aged 14-15 years) in UK schools. Schools were randomly allocated (1:1) and masked to allocation at baseline. The primary outcome was self-reported avoidance of unprotected sex (sexual abstinence or use of reliable contraception at last sex) after 12-14-months. We analysed the data using intention-to-treat mixed effects regression models.Of 803 schools assessed for eligibility, 263 schools were invited by letter, of which 66 schools agreed to be randomly assigned, of which 62 schools completed follow-up. The trial was done between Feb 1, 2018, and March 6, 2020. 8216 students participated at baseline in 2018; 6561 (79·85%) provided 12-14 months follow-up. There was no significant difference in the primary outcome of avoidance of unprotected sex: 2648 (86·62) of 3057 in the intervention group avoided unprotected sex versus 2768 (86·41%) of 3203 in the control group (adjusted odds ratio [aOR] 0·85 [95% CI 0·58-1·26], p=0·42). Exploratory post-hoc analysis of the two components of the primary outcome showed that significantly more intervention students used reliable contraception at last sex compared with control students and there was no significant difference between the groups for sexual abstinence. No adverse events were reported.The intervention had a null effect on the primary outcome of preventing unprotected sex (increasing sexual abstinence or use of reliable contraception) in the whole student population. However, the results showed significant increases in use of reliable contraceptives for sexually active students. Engaging all young people early through RSE is important so that as they become sexually active, rates of unprotected sex are reduced.National Institute for Health Research.
Triage in general practice: more impersonal, industrialised medicine
Authors: Peter W Ward
Journal: BMJ (2022)

<h3>Background:</h3> Respiratory tract infections (RTIs) account for 60% of antibiotic prescribing in primary care. Several clinical prediction rules (CPRs) have been developed to help reduce unnecessary prescribing for RTIs, but there are a lack of studies exploring whether or how these CPRs are being used in UK general practice. <h3>Aim:</h3> To explore UK GPs’ views and experiences with regards to RTI CPRs and to identify barriers and facilitators to their use in practice. <h3>Design &amp; setting:</h3> A qualitative analysis of interviews with in-hours GPs working in the South and South West of England. <h3>Method:</h3> Semi-structured qualitative telephone interviews were conducted, digitally recorded, transcribed verbatim and analysed using an inductive thematic approach. Patient and public involvement representatives contributed to study design and interpretation of findings. <h3>Results:</h3> Thirty-two GPs were interviewed. Some CPRs were more commonly used than others. Participants used CPRs to facilitate patient-clinician discussion, confirm and support their decision, and document the consultation. GPs also highlighted concerns including lack of time, inability of CPRs to incorporate patient complexity, a shift in focus from the patient during consultations, and limited use in remote consultation (during the COVID-19 pandemic). <h3>Conclusion:</h3> This study highlights the need for user-friendly CPRs that are readily integrated into computer systems, and easily embedded into routine practice to complement clinical decision making. Existing CPRs need to be validated for other populations where demographics and clinical characteristics may differ as well different settings including remote consultations and self-assessment.
Exploring the clinical and genetic associations of adult weight trajectories using electronic health records in a racially diverse biobank: a phenome-wide and polygenic risk study
Authors: Jiayi Xu, Jessica S Johnson, Rebecca Signer, Andreas Birgegård, Jennifer Jordan, Martin A Kennedy, Mikael Landén, Sarah L Maguire, Nicholas G Martin, Preben Bo Mortensen, Liselotte V Petersen, Laura M Thornton, Cynthia M Bulik, Laura M Huckins
Journal: The Lancet Digital Health (2022)

Weight trajectories might reflect individual health status. In this study, we aimed to examine the clinical and genetic associations of adult weight trajectories using electronic health records (EHRs) in the BioMe Biobank.
Tumor immune microenvironment of primary prostate cancer with and without germline mutations in homologous recombination repair genes
Authors: Anna Sofia Trigos, Anupama Pasam, Patricia Banks, Roslyn Wallace, Christina Guo, Simon Keam, Heather Thorne, Catherine Mitchell, Stephen Lade, David Clouston, Alexander Hakansson, Yang Liu, Benjamin Blyth, Declan Murphy, Nathan Lawrentschuk, Damien Bolton, Daniel Moon, Phil Darcy, Ygal Haupt, Scott G Williams, Elena Castro, David Olmos, David Goode, Paul Neeson, Shahneen Sandhu
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Aberrations in homologous recombination repair (HRR) genes are emerging as important biomarkers for personalized treatment in prostate cancer (PCa). HRR deficiency (HRD) could affect the tumor immune microenvironment (TIME), potentially contributing to differential responses to poly ADP-ribose polymerase (PARP) inhibitors and immune checkpoint inhibitors. Spatial distribution of immune cells in a range of cancers identifies novel disease subtypes and is related to prognosis. In this study we aimed to determine the differences in the TIME of PCa with and without germline ( g ) HRR mutations. Methods We performed gene expression analysis, multiplex immunohistochemistry of T and B cells and quantitative spatial analysis of PCa samples from 36 patients with g HRD and 26 patients with sporadic PCa. Samples were archival tumor tissue from radical prostatectomies with the exception of one biopsy. Results were validated in several independent cohorts. Results Although the composition of the T cell and B cells was similar in the tumor areas of g HRD-mutated and sporadic tumors, the spatial profiles differed between these cohorts. We describe two T-cell spatial profiles across primary PCa, a clustered immune spatial (CIS) profile characterized by dense clusters of CD4 + T cells closely interacting with PD-L1 + cells, and a free immune spatial (FIS) profile of CD8 + cells in close proximity to tumor cells. g HRD tumors had a more T-cell inflamed microenvironment than sporadic tumors. The CIS profile was mainly observed in sporadic tumors, whereas a FIS profile was enriched in g HRD tumors. A FIS profile was associated with lower Gleason scores, smaller tumors and longer time to biochemical recurrence and metastasis. Conclusions g HRD-mutated tumors have a distinct immune microenvironment compared with sporadic tumors. Spatial profiling of T-cells provides additional information beyond T-cell density and is associated with time to biochemical recurrence, time to metastasis, tumor size and Gleason scores.
Abnormal metaphase cytogenetics predicts venous thromboembolism in myeloma: derivation and validation of the PRISM score
Authors: Rajshekhar Chakraborty, Lisa Rybicki, Wei Wei, Jason Valent, Beth M. Faiman, Christy J. Samaras, Faiz Anwer, Alok A. Khorana
Journal: Blood (2022)
PB2285: CLINICAL EXPERIENCE WITH CEFTAZIDIME-AVIBACTAM FOR THE TREATMENT OF BACTEREMIA DUE TO CARBAPENEM-RESISTANT GRAM-NEGATIVE BACTERIA IN HEMATOLOGIC PATIENTS
Authors: S. Zhen, S. Feng, W. Zhai
Journal: HemaSphere (2022)

Background: Experience on effectiveness of ceftazidime-avibactam (CAZ-AVI) for bacteremia caused by carbapenem-resistant gram-negative bacteria in hematologic patients is scare. Aims: We conducted this cohort to evaluate the effectiveness and safety of CAZ-AVI for this population, and also, to explore the predictors of clinical outcome. Methods: We performed a retrospective, observational study at a blood diseases hospital in China for patients who received ≥ 72 h of CAZ-AVI for bloodstream infections due to carbapenem-resistant Enterobacteriacea and Pseudomonas aeruginosa between November 2018 and June 2021. Clinical and microbiological characteristics of these patients were collected; clinical and microbiological outcomes, occurrence of adverse effect were assessed. We compared the survival between transplant and nontransplant patients, also between patients who did or did not undergo granulocyte recovery within 14 days. We used Kaplan-Meier survival estimates to generate survival curves. To identify predictors of survival and clinical success, univariate and multivariate analysis was performed. Results: Forty-seven patients were eligible for our study. Forty (85.1%) patients received combination therapy, while seven received CAZ-AVI monotherapy. All patients infected with MBL (metallo-β-lactamase)-CRE (carbapenem-resistant Enterobacteriaceae) (n=23) received combination therapy with aztreonam. The survival at 28 days was 83.0% in 47 patients, and was 91.3% (21/23) in patients with MBL-CRE bacteremia. Clinical success was observed in 35/47 (74.5%) patients. Multivariate analysis revealed the most significant factor of clinical success was the granulocyte recovery within 14 days. Summary/Conclusion: CAZ-AVI-containing regimen is an effective option for the bacteremia due to carbapenem-resistant Gram-negative bacteria among hematologic patients, even in those infected with MBL-CRE bacteremia. Appropriate combination therapy is important after acquiring the information of enzymes and susceptibility to CAZ-AVI in vitro. Granulocyte recovery within 14 days may be a predictor of clinical success.
PB2322: TTP AFTER COVID 19
Authors: D. Gagloeva, E. Zhelnova
Journal: HemaSphere (2022)

Background: It is widely known that viruses can cause autoimmune disorders. Since 2019 medical community has been convinced, that SARS COV2 can also initiate such autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis, antiphospholipid syndrome, etc. In our hospital we faced a clinical case of thrombotic thrombocytopenic purpura (TTP) after vaccination and SARS COV2 – infection Aims: to clarify more possible autoimmune disorders induced by COVID 19 and complications after vaccination against SARS COV2 Methods: A 72-year-old man was admitted to hematological department in August 2021 because of rapidly worsening general condition, hemolytic anemia (hemoglobin 6.82 mmol/l, hematocrit 1,28), and thrombocytopenia (28 Gpt/l) for unknown reasons. Additionally, he was found to have an elevated lactate dehydrogenase (63.42 μmol/l/s) and bilirubin (86 μkmol/l/s). Direct and indirect Coombs test were negative. He was also presented with cognitive defects and neurologic disorders. It is known from the case history, that he had been vaccinated against SARS COV2 with one of the Russian vaccines one months before admitting to our clinic. After that he was admitted to the hospital with SARS COV2 –associated pneumoniae. He underwent a course of therapy, including anticoagulants and IL-6 inhibitors. When pneumonia regressed, he was discharged. But one week later he started to feel worse. We suggested autoimmune hemolytic anemia and gave him steroid pulse therapy according to vital indications, with no improvement. The differential diagnostic was continued among hemolytic-uremic syndrome, TTP, cancer, autoimmune disorder and viral infections. We detected extremely low level of protease ADAMTS13 (5%) and diagnosed TTP. We started daily plasma exchange #15, which ended with complete remission of the disease – total regress of cognitive defects and neurologic disorders, rapid raise of thrombocyte level and hemoglobin. Results: Our patient was completely cured. We have 6 months of observation data on him. There were no relapses of TTP during this time. The cause of manifestation of the TPP in 72 year- old patient remained unclear. To date, there are more and more cases of autoimmune diseases after vaccination and COVID 19. In particular, one similar case of TTP after Pfizer vaccine injection was already described. Summary/Conclusion: Thus, previous vaccination and coronavirus infection, could be the possible causes of TTP in this case. However, another equally important question still remains open – what exactly contributed to autoimmunization - vaccination or COVID 19. Further research is required. That is why more careful selection of patients for vaccination is required.